441713-62-8Relevant articles and documents
Discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido) phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid: An orally active, selective very late antigen-4 antagonist
Muro, Fumihito,Iimura, Shin,Sugimoto, Yuuichi,Yoneda, Yoshiyuki,Chiba, Jun,Watanabe, Toshiyuki,Setoguchi, Masaki,Iigou, Yutaka,Matsumoto, Keiko,Satoh, Atsushi,Takayama, Gensuke,Taira, Tomoe,Yokoyama, Mika,Takashi, Tohru,Nakayama, Atsushi,Machinaga, Nobuo
experimental part, p. 7974 - 7992 (2010/09/03)
We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3- indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-( 2S)-pyrrolidinylmethoxy] cyclohexanecarboxylic acid (14e) with potent activity (IC50 = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
